1,1-disubstituted-2-alkyl isoindolines

ABSTRACT

1,1-disubstituted-2-alkyl isoindolines, e.g. 1,1-diphenyl-2methyl isoindoline, are prepared by treating a corresponding isoindolinone with mild reducing agent. The compounds are useful as analgesics.

United States Patent 191- Houlihan et al.

[ June 26, 1973 .1 ,l-DISUBSTITUTED-Z-ALKYL ISOINDOLINES Inventors:William J. Houlihan, Mountain Lakes; Jeffrey Nadelson, Parsippany,

both of NJ.

Assignee: Sandoz-Wander, lnc., Hanover, NJ.

Filed: Sept. 22, 1970 Appl. No.2 74,467

US. Cl. 260/326.1, 260/295 K, 260/295 AM, 260/296 B, 260/325, 260/332.2A, 260/322.3 P, 260/346.2 R, 260/347.3, 424/263, 424/274 Int. Cl. C07d27/48, C07d 27/50 Field of Search 260/326.1

References Cited 7 UNITED STATES PATENTS 2,381,000 4/l968 Drurkeretal..260/326.1X

Primary Examiner-Joseph A. Narcavage 4 Attorney-Gerald D.- Sharkin,Fredericklli Weinfeldt, Robert S. Honor, Walter F. Jewell and Richard E.,Vila

3 Claims, No Drawings 1 i 2 l,l-DlSUBSTITUTED-Z-ALKYL ISOINDOLINESAccording to this aspect, of the invention, the com- This inventionrelates to isoindolines. More particupounds offormula ,(l) are preparedby reducing a comlarly, it relates to l-phenyl or substitutedphenyl-l-arylpound of formula (II) with a mild reducing agent, par-2-alkyl isoindolines, acid addition salts and intermediticularly metalhydride, e.g. lithium aluminum hydride, ates thereof, and processes forthe preparation of these 5 diisobutyl-aluminum hydride, diborane, orsodium bismaterials. (Z-methoxyethoxy) aluminum hydride, in inertsolvent The compounds of this invention may be represented and inertatmosphere, e.g. nitrogen gas, at a temperaby the following structuralformula: ture of from about l0C. to 150C, conveniently at the refluxtemperature of the system, for about to 48 10 hours, preferably about 18to 24 hours, Solvents which I I I I l H I n may be used include etherssuch as ethyl ether or tetrahydrofuran, or hydrocarbon solvents such asbenzene, toluene and the like. The temperature, reaction times andsolvents used are not critical. The compounds of x l5 formula (I) may berecovered using conventional recovery techniques such ascrystallization.

' The compounds of formula (H), a further aspect of R2 this invention,may be prepared according to the following reaction scheme:

Mai? \v 1 wherein Y R1- 1 R represents primary and secondary loweralkyl,i.e. A

primary and secondary alkyl having 1-5 carbon 25 R1 Ar R1 r atoms suchas methyl, ethyl, and isopropyl; each R,, independently, representshydrogen, halo 0 R-N having an atomic weight of 19 to 36, trifluoro- 4hmethyl, lower-alkoxy, i.e. alkoxy having I 5 carbon atoms, e.g. methoxy,ethoxy, propoxy, iso- I l propoxy, butoxy, isobutoxy and the like orloweral- (m) m kyl, i.e. alkyl having l-5 carbon atoms such as 1 methyl,ethyl, propyl, isopropyl and the like; or two of R together representmethylenedioxy, prov wherein R, R 'R R Ar and the provisos have thevided they are on adjacent carbon atoms, above-stated significance. v

R represents hydrogen, trifluoromethyl, lower alkyl, Compounds (ll) areprepared by treating compounds as previously defined, or lower alkoxy aspreviously ([11) with strong mineral acid such as hydrohalic acid,defined; e.g, hydrochloric acid, at about 40-l00C, conve- R representshydrogen, halo having an atomic niently at the reflux temperature of thesystem, for

weight of 19 to 36, or lower alkoxy as previously 40 about l224 hours.Neither the reaction time'nor temdefined; perature are critical, andsolvent is not required. The and 7 compounds (II) are then recoveredusing conventional Ar represents phenyl, pyridyl (2,3 and 4), thienyl (2techniques, e.g., filtrationand recrystallization. and 3), furyl (2 and3) and naphthyl and 2); The compounds (III) are prepared according tothe provided no two trifluorornethyl groups are on adjacent followingreaction scheme: I carbon atoms, provided also that no more than threeof 1 R R and R are other than hydrogen and that no more g a. than two ofR,, R and R are other than hydrogen in one ring. a The compounds offormula (I) may be prepared as represented by the following reactionscheme: R1 1 M I 7 h v I -m R1 R1 R1 O 1 H -11: Rz It; I R] RN I i I I AA B3 I m It 'ld d i It 1 f m agein mg A (IV) a R (m) u i R- Thecompounds of formula (III) are prepared by cyclizing a compound offormula (IV) in an aqueous or non-aqueous media with mineral acid, suchas sulfuric acid, a hydrohalic acid such as hydrochloric or hydrobromicacid, phosphoric acid and thelike, at a temperature of from about to C.,conveniently at the wherein R, R R R and Ar and the provisos have thereflux temperature-of the system. More preferably, an'd above-statedsignificance. for generally improved yields, the compounds (III) may beprepared from compounds of formula IV) by treatment with organic acidsor their anhydrides, such as acetic acid, trifluoroacetic acid, aceticacid anhydride, trifluoroacetic acid anhydride and the like, at atemperature of about l to C., preferably to +5C. The anhydrides arepreferred and trifluoroacetic acid anhydride is a particularly preferredcyclizing agent.

The reaction is suitably conducted for about 1-48 hours, preferably24-48 hours for the mineral acids and 1-24 hours for the organic acidsor their anhydrides. The presence of solvent is not necessary andgenerally is not desired since it could interfere with the obtaining ofthe compounds (III). To improve yields and obtain a better qualityproduct, the reaction may be performed under inert atmosphere, e.g.nitrogen gas. Neither the time nor temperature of reaction is critical.Compounds(III) may be recovered using conventional recovery techniques,such as filtration.

The compounds (III) are novel except in that instance where Arrepresents phenyl, R represents methyl and all other variablesubstituents represent hydrogen.

According to a still further aspect of this invention, compounds (IV),new and novel except where Ar is phenyl, R is methyl and all othersubstituents are hydrogen, may be prepared as illustrated in thefollowing reaction scheme from compounds (V) and (VI).

R1 Li R R1 AI Rz R-N II 8 R3 (VI) HO R1 R s 1 R3 where R, R R R Ar andthe provisos have the above stated significance.

Compounds (IV) may be prepared by condensing a compound (V) with acompound (VI) in an inert solvent such as ethers, e.g. diethyl ether ortetrahydrofuran, or hydrocarbons or aromatic hydrocarbons such ashexane, heptane, benzene, toluene and the like. This condensation may becarried out'at a temperature of from about to +IOC, preferably 5 to +5Cfor about I to 3 hours. The exact time and temperature of reaction andthe particular solvent used is not critical. The resulting reactionproduct is then hydrolyzed, preferably by adding the reaction mixture towater or ice or aqueous solutions normally used for hydrolysis, e.g.,ammonium chloride solution, at about 0 to 10C. The product may then beused directly for the preparation of compounds (III).

Itwill be understood that certain of the compounds of formulas (I),(II), (III) and (IV)-exist in racemic form or in the form of opticallyactive isomers. The separation of the respective isomers may beaccomplished employing conventional techniques and such isomers areincluded within the scope of the invention.

Certain of the compounds of formulae (V) and (VI) are known and may beprepared by methods described in the literature. Those compounds offormulae (V) and (VI) not specifically described may be prepared byanalogous methods from known materials.

The compounds of formula (I) are useful because they possesspharmacological activity in animals, such as mamals. In particular, thecompounds possess analgesic activity as indicated by their activity inmice at 25 mg/kg orally when tested using the "Hot-Plate method ofWoolfe and McDonald (J. Pharmacol. & Exper. Therap. :300, 1944).

When so utilized, the compounds may be combined with one or morepharmaceutically acceptable carriers or adjuvants. Depending upon theparticular active compound employed, the exact dosage utilized may vary.

Furthermore, the compounds of formula (I) may be similarly administeredin the form of their non-toxic pharmaceutically acceptable acid additionsalts. Such salts possess the same order of activity as the free base,are readily prepared by reacting the base with an appropriate acid andaccordingly are included within the scope of the invention.Representative of such salts are the mineral acid salts, such as thehydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts, such as the succinate, benzoate, acetate,p-toluenesulfonate, benzenesulfonate and the like.

In general, satisfactory results are obtained when the compounds areadministered orally at a daily dosage of from about 0.1 mg/kg of animalbody weight, preferably given in divided doses, 24 times a day or insustained release form. For most larger mammals (e.g., primates) thetotal daily dosage is from about 5 milligrams to about 400 milligrams.Dosage forms suitable for internal use comprise from about 1.5milligrams to about 200 milligrams of the active compound in intimateadmixture with a solid or liquid pharmaceutically acceptable carrier ordiluent.

A representative formulation suitable for oral administration is acapsule prepared by standard techniques which contains the followingIngredients: Parts by weight l,I-diphenyl-2-methyl isoindoline 25 Inertfiller (starch, kaolin, lactose, etc.) 275 As noted above, the compoundsof formula (I) exist as optical isomers. In some cases greaterpharmacological activity or other beneficial attribute may be found fora particular isomer and in some instances administration of such isomermay be preferred.

The preferred compounds of formula (I) are those wherein Ar, R and R, onthe isoindoline moiety are as previously defined and all othersubstitutents represent hydrogen.

The corresponding compounds of formulae (II), (III) and (IV) aresimilarly preferred.

EXAMPLE I a,a-Diphenyl-a-hydroxy-N-methyl-o-toluamide To a flaskequipped with a stirrer, dropping funnel, condenser and gas inlet tubemaintained under a nitrogen atmosphere there is added at roomtemperature 15.2 g. (0.018 mole) of N-methyl benzamide and 150 ml. ofdry tetrahydrofuran. The reaction flask is immersed in an ice bath andcooled to an internal temperature of 5C. Stirring is initiated and 152ml. of 1.6 M n-butyllithium (0.24 mole) in hexane is added dropwise inca 1 hour maintaining the temperature below 8C. The resulting dilithiosalt is stirred at 5C. for an additional hour and then a solution of19.6 g (0.108inole) of benzophenone in 75 ml. of anhydroustetrahydrofuran is added dropwise in ca 45 min. maintaining thetemperature between -l and 10C. The resulting mixture is stirred at C.for 1 hour longer and then poured with stirring onto 300 g. of ice whilemaintaining the temperature below C. The layers areseparated, thetetrahydrofuran layer dried over anhydrous magnesium sulfate, andfiltered and evaporated in vacuo. The resulting oil is triturated withcold ethyl ether and filtered to give crude a,a-diphenyl-ae.a-hydroxy-a-(2-naphthyl)-a-(ptrifluoromethylphenyl)-N-methyl-o-t0luamide, or f.a-hydroxy-a( 3,4-methylenedioxyphenyl)-aphenyl-N-methyl-o-toluamide,respectively.

When the above process is carried out and o-chloro- N -methyl benzamideor N -ethyl-m-methoxy benzamide is used in place of N-methyl benzamide,there is obtained 6-chloro-a,a-diphenyl-a-hydroxy-N-methyl-2rtoluamide,or' a,a-diphenyl-a-hydroxy-5-methoxy-N- ethyl-2-toluamide,respectively.

EXAMPLE 2 3 ,3-Diphenyl- 1 -methylimino phthalan To a flask equippedwith a stirrer, condenser and gas inlet tube maintained under a nitrogenatmosphere there is added at room temperature 100 g. of trifluoroaceticacid anhydride. The flask is cooled to an internal temperature of 0C.and g. of the crude a,a-diphenyl-a-hydroxy-Nmethyl-o-toluamide obtainedin Example l is added in portions with stirring. The reaction mixture ismaintained at- 0C. for l hour,at room temperature for l8 hours, and isthen evaporated in vacuo. The residue is dissolved in methylene chlorideand washed with 100 ml. of water, 100 ml. of 2N sodium hydroxide andagain 100 ml. of water, dried over magnesium' sulfate, filtered andevaporated in vacuo. The resulting solid is triturated with cold ethylether and the ether insoluble material is recrystallized from hotethylacetate to give 3,3-diphenyl-1-methylimino phthalan. When the aboveprocedure is carried out and a.a-hydroxy-a-phenyl-a(m-tolyl)-N-methyl-otoluamide, b.a-hydroxy-a-phenyl-a( 2-pyridyl )-N-methyl-otoluamide, 5 c.a-hydroxy-a-(p-methoxyphenyl)-a-(2-thienyl)-N- methyl-o-toluamide, d.a-hydroxy-a-( p-chlorophenyl )-a-( 3-furyl )-N- methyl-o-toluamide,a-hydroxy-a-(2-naphthyl)-a-(ptrifluoromethylplienyl)-N-methyl-o-toluamide,f. a-hydroxy-a(3,4-methylenedioxyphenyl)-aphenyl-N-methyl-o-toluamide,g. 6-chloro-a,a-diphenyl-a-hydroxy-N-methyl-2- toluamide, or

a,a-diphenyl-a-hydroxy-5-methoxy-N-ethyl-2- toluamide is used in placeof a,a-diphenyl-a-hydroxy-N-methyl-otoluamide, there is obtained a.l-methylimino-3-phenyl-3-(m-tolyl)phthalan, b.l-methylimino-3-phenyl-3-(2-pyridyl )phthalan, c. 3-( p-methoxyphenyl l-methylimino-3-( 2- thienyl)phthalan,3-(p-chlorophenyl)-3-(3-furyl)-lmethyliminophthalan, e.1-methylimino-3-(2-naphthyl)-3-(p-trifluoromethylphenyl)phthalan, f.l-methylimino-3-( 3 ,4-methylenedioxyphenyl)-3- phenyl phthalan, g.5-chloro-3 ,3-diphenyll -methyliminophthalan, or h.3,3-diphenyl-l-ethylimino-6-methoxy phthalan,

respectively.

EXAMPLE 3 l l -Diphenyl-2-methyl isoindoline-3-one A mixture of 36.7 g.of 3,3-diphenyl-l-methylimino phthalan and 400 ml. of 2N hydrochloricacid is heated at reflux for 18 hours. The mixture is then cooled andfiltered, and the resulting solid is washed with water, dissolved inmethylene chloride and dried with magnesium sulfate. The solution isthen filtered, evaporated and the resulting solid is recrystallized fromhot ethyl acetate to give 1,1-diphenyl-2-methyl isoindoline- 3-one.

When the above procedure is used and in place of3,3-diphenyl-l-methylimino phthalan there is used a.l-methylimino-3-phenyl-3-(m-tolyl)phthalan, b.l-methylimino-3-phenyl-3-( 2-pyridyl)phthalan, c. 3-(p-methoxyphenyl)- l-methylimino-3-( 2- thienyl)phthalan, d. 3-(p-chlorophenyl)-3-(3-furyl)- l-methylimino phthalan, e.l-methylimino-3-(2-naphthyl)-3-(p-trifluoromethylphenyl)phthalan, I f.l-methylimino-3-(3,4-methylenedioxyphenyl)-3- phenylphthalan, g.5-chloro-3,3-diphenyl-l-methyliminophthalan, or h. 3,3-diphenyl-l-ethylimino-6-methoxyphthalan, there is obtained a. 2-methyll -phenyllm-tolyl)isoindoline-3-one, b. 2-methyll -phenyll 2-pyridyl)isbindoline-B-one, c.1-(p-methoxyphenyl)-2-methyl-l-(2-thienyl)isoindoline-3-one, d.l-(p-chlorophenyU-l-(3-furyl)-2-methyl isoindoline-3-one,

2-methyll 2-naphthyl)- l ptrifluoromethylphenyl)isoindoline-S-one,

7 f. Z-methyll-( 3,4-methylenedioxyphenyl)- 1 -phenyl isoindoline-3-one,g. 6-chloro-l ,l-diphenyl-2-methyl isoindoline-3-one,

or h. 1,1-diphenyl-2-ethyl-5-methoxy isoindoline-B-one,

respectively.

EXAMPLE 4 l l-Diphenyl-Z-methyl isoindoline To a flask equipped with astirrer, condenser, and gas inlet tube maintained under a nitrogenatmosphere there is added at room temperature 1.14 g. (0.03 mole) oflithium aluminum hydride and 50 ml. of anhydrous tetrahydrofuran.Stirring is initiated and a solution of 6.3 g. (0.021 mole) ofl,l-diphenyl-2-methyl isoindoline-3-one in 120 ml. of anhydroustetrahydrofuran is added dropwise in ca. 30 minutes. The resultingmixture is refluxed for 18 hours and cooled in an ice bath. Ethylacetate(6.8 ml) is added dropwise in ca. 10 minutes, followed by the dropwiseaddition of 2.3 ml. of 2N of sodium hydroxide in ca. 10 minutes and thedropwise addition of 3.4 ml. of water in ca. 10 minutes. The resultingmixture is dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to give a semisolid which is triturated with hotether. The filtrate is evaporated in vacuo and the residuerecrystallized from pet. ether to give l,l-diphenyl-2-methylisoindoline; m.p. 102-l04.5C.

When the above process is carried out and in place of1,1-diphenyl-2-methyl isoindoline-3-one there is used a. Z-methyll-phenyll -(m-tolyl)isoindoline-3-one,

b. 2-methy1-l -phenyll -(Z-pyridyl)isoindoline-3-one,

c. 1-(p-methoxyphenyl)-2-methyl-1-(2-thienyl)isoindoline-3-one,

d. l-(p-chlorophenyl)-1-(3-furyl)-2-methyl isoindoline-3-one,

e. Z-methyll 2-naphthyl)- l -(ptrifluoromethylphenyl)isoindoline-3-one,f. 2-methyll 3 ,4-methylenedioxyphenyl)- l -phenyl isoindoline-3-one, g.6-chl0ro-l ,1-diphenyl-2-methyl isoindoline-3-one,

or h. l, l -diphenyl-2-ethyl-5 -methoxy isoindoline-B-one,

there is obtained a. 2-methyll -phenyll -(m-tolyl)isoindoline,

b. 2-methyl-1-phenyl-1-(2-pyridyl)isoindoline,

c. l-(p-methoxyphenyl)-2-methyl-l-(2- thienyl)isindoline,

d. l-(p-chlorophenyl)-l-(3-furyl)-2-methyl isoindoline,

e. 2-methyl-l-(2-naphthyl)-1-(p-trifluoromethylphenyl)isoindoline,

f. 2-methyl-l-(3,4-methylenedioxyphenyl)-1-phenyl isoindoline,

g. 6-chloro-l,l-diphenyl-2-methyl isoindoline, or h.l,l-diphenyl-2-ethyl-5-methoxy isoindoline, re-

spectively. What is claimed is:

R represents primary and secondary loweralkyl, each R independently,represents hydrogen, halo having an atomic weight of 19 to 36,trifluoromethyl, lower alkoxy or lower alkyl; or two of R togetherrepresent methylenedioxy, provided they are on adjacent carbon atoms;

R represents hydrogen, trifluoromethyl, loweralkoxy or lower alkyl;

R represents hydrogen, halo having an atomic weight of 19-36, or loweralkoxy; and

Ar represents phenyl, pyridyl, thienyl, furyl or naphthyl;

provided no two trifluoromethyl groups are on adjacent carbon atoms,provided also that no more than three of R R and R are other thanhydrogen, and that no more than two of R R and R are other than hydrogenin one ring, or a pharmaceutically acceptable acid addition saltthereof.

2. A compound according to claim 1 which is l,l-diphenyl-2-methylisoindoline.

3. A compound of the formula

2. A compound according to claim 1 which is 1,1-diphenyl-2-methyl isoindoline.
 3. A compound of the formula 